Peptides play vital roles by mediating a wide range of biological processes, acting as hormones, antibiotics, and signaling molecules. Due to the highly specific interaction with their biological targets, peptides have been widely used in medicine. However, the enormous therapeutic potential of peptides is not always easy to realize due to their low bioavailability. This shortcoming is a consequence of the degradation of peptides by endo- and exopeptididases, which results in poor in vivo stability of peptides. Compared to their linear counterparts, cyclic peptides are more resistant to degradation. There are two main reasons for this stability. Firstly, exopeptidases cannot cleave the cyclic peptide at its (non-existent) ends. Secondly, cyclic peptides, especially those with a small-to-medium ring size, are protected against endopeptidases because the constrained cyclic peptide backbone prevents the adaptation of the required extended conformation during proteolysis. In addition, the reduced charge and intramolecular hydrogen bonding within cyclic peptides facilitate passive membrane permeability, which contributes to their enhanced bioavailability. Most significantly, conformational constraints imposed on the amino acid sequence by the cyclic topology maximize enthalpic interactions between cyclic peptides and their biochemical targets while ensuring favourable entropy of binding.
There has been enormous interest in both naturally occurring and synthetic cyclic peptides as scaffolds that pre-organize an amino acid sequence into a rigid conformation.1 Amongst the vast number of known cyclic peptides, rigid small-to-medium sized rings have been of particular interest. Various cyclolactamization and non-peptidic cyclization methods2 have been developed.
The macrocyclization of linear precursors is afflicted by several thermodynamic and kinetic challenges that arise from the conformational preferences of linear peptides. The chain/ring conformational equilibrium is the central obstacle facing synthesis of cyclic molecules from acyclic precursors. Short linear peptides can easily adopt a circular conformation, which is driven by ion pairing between the N- and C-termini (Scheme 1, A).3 Despite the unfavorable entropy, these circular conformations are thermodynamically favoured due to the enthalpy garnered through electrostatic and other polar interactions. As shown in Scheme 1, conventional activation reagents tend to remove the zwitterionic character of the peptide, rendering it incapable of forming ion pairs. Consequently, without enthalpic contribution from electrostatics and other polar interactions, the activated peptide adopts a random linear conformation (Scheme 1, B). In order for macrocyclization to occur, the activated peptide must adopt a pre-cyclization conformation (C) prior to forming the desired cyclic molecule (D). High dilution, on the order of 10−4 or greater, is essential to limiting the formation of by-products arising from cyclodimerization,4 cyclotrimerization, and polymerization.5 Unfortunately, dilution brings about long reaction times, which in turn provoke background processes such as epimerization. Amongst the most challenging cyclizations are those attempted on linear peptides containing less than seven residues.6,7

Another common challenge in exploring macrocyclic chemistry space has to do with late-stage modification. This is a historic challenge for macrocyclic compound libraries built in the biotechnology and pharmaceutical companies. Their typical cyclization techniques (ring-closing metathesis, Huisgen cycloaddition) do not naturally lend themselves to further elaboration. Functional group handles must be built in prior to cyclization to achieve this goal.